The present invention is generally related to novel 2H-tetrazole-5-yl amide compounds, a process for making the compounds, a medicament incorporating the compounds and a method of treatment utilizing the compounds as metabotropic glutamate receptor agonists.
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor. L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors. At present, eight different members of these mGluRs"" are known and of these some even have sub-types. On the basis of structural parameters, the different second messager signalling pathways and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups:
mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits, as well as chronic and acute pain. Other treatable indications by administration of agonists of metabotropic gluamate receptors include restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The present invention is includes 2H-tetrazole-5-yl-amide derivatives of the formula 
wherein
R1 is hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94CF3, xe2x80x94(CH2)nxe2x80x94CHF2, xe2x80x94(CH2)nxe2x80x94CN, xe2x80x94(CH2)n-cycloalkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)nxe2x80x94O-cycloalkyl or xe2x80x94(CH2)nxe2x80x94C(O)O-lower alkyl;
R2 is hydrogen, lower alkyl, lower alkoxy, halogen, xe2x80x94C(O)-lower alkyl, xe2x80x94C(O)OH, xe2x80x94C(O)O-lower alkyl, xe2x80x94NR3R4 or xe2x80x94C(O)xe2x80x94NR3R4 and wherein R3 and R4 are hydrogen or lower alkyl;
X and Xxe2x80x2 are taken together to form xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2, xe2x80x94OCH2xe2x80x94, a bridge between the two rings or individually are two hydrogen atoms not capable of forming a bridge between the two rings; and
n signifies 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
A compound of structure I and a pharmaceutically acceptable salt thereof are novel and are distinguished by valuable therapeutic properties.
It has been surprisingly found that the compounds of formula I are group 1 metabotropic glutamate receptor agonists (mGluR).
A preferred compound of formula 1 has the structure formula 1A 
Preferred compounds having structure 1A include compounds having R1 being lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)O-lower alkyl, xe2x80x94(CH2)n-cycloalkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)nxe2x80x94CF3, xe2x80x94(CH2)nxe2x80x94CHF2, or xe2x80x94(CH2)nxe2x80x94CN and R2 being hydrogen.
The following are examples of preferred compounds having the structure of formula 1A:
N-(2-methyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-ethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-cyclopropylmethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-isopropyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
2,2-diphenyl-N-[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-acetamide,
2,2-diphenyl-N-(2-propyl-2H-tetrazol-5-yl)-acetamide,
N-(2-methoxymethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-tert-butyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-difluoromethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-cyanomethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide and
(5-diphenylacetylamino-tetrazol-2-yl)-acetic acid methyl ester.
Another preferred compound of formula 1 has the structure 1B 
wherein X and Xxe2x80x2 are joined together as xe2x80x94Oxe2x80x94 thereby forming a bridge between the rings.
Preferred compounds having structure 1B include compounds having R1 being lower alkyl, xe2x80x94( CH2)n-cycloalkyl, xe2x80x94(CH2)nxe2x80x94CF3, xe2x80x94(CH2)nxe2x80x94CHF2, xe2x80x94(CH2)nxe2x80x94CN, xe2x80x94(CH2)nxe2x80x94C(O)O-lower alkyl or xe2x80x94(CH2)nxe2x80x94O-lower alkyl and R2 being hydrogen and R1 being lower alkyl and R2 being lower alkoxy.
The following are examples of preferred compounds having the structure 1B:
9H-xanthene-9-carboxylic acid (2-methyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-cyclopropylmethyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-isopropyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid [2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-amide,
9H-xanthene-9-carboxylic acid (2-propyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-methoxymethyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-tert-butyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-difluoromethyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-cyanomethyl-2H-tetrazol-5-yl)-amide,
{5-[(9H-xanthene-9-carbonyl)-amino]-tetrazol-2-yl}-acetic acid methyl ester,
(RS)-1-methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide,
(RS)-2-methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide and
(RS)-4-Methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide
Another preferred compound from formula 1 is a compound with the structure of formula 1C. 
wherein X and Xxe2x80x2 are joined together as xe2x80x94Sxe2x80x94, thereby forming a bridge between the rings. A preferred example of the compound of formula 1C is 9H-thioxanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
Yet another preferred compound of formula 1 has the structure 1D. 
wherein X and Xxe2x80x2 are joined together as xe2x80x94CH2xe2x80x94, thereby forming a bridge between the rings. A preferred example of a compound with the structure of formula 1D is 9,10-dihydro-anthracene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
Another preferred compound of formula I has the structure IE 
wherein X and Xxe2x80x2 are joined together as xe2x80x94OCH2xe2x80x94, thereby forming a bridge between the rings; and wherein R1 and R2 are as defined in formula I above. A preferred compound of formula 1E is (RS)-6,11-dihydro-dibenzo [b,e]oxepine-11-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
Also preferred are compounds of the present invention of formula IA, IB, IC, ID and IE, wherein R2 is hydrogen.
The compound of the invention embraces all stereoisomeric forms of formula I in addition to the racemates.
The term xe2x80x9clower alkylxe2x80x9d used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
The term xe2x80x9ccycloalkylxe2x80x9d embraces cyclic alkyl rings having between 3 to 7 carbon atoms.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by processes, which comprises 
with a compound of formula 
to a compound of formula 
wherein the substituents are as designated above and, if desired, converting a functional group in a compound of formula I into another functional group and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
In accordance with process variant described above to a stirred solution of a compound of formula II, for example of 5-amino-2-methyl-2H-tetrazole, 5-amino-2-ethyl-2H-tetrazole or 5-amino-2-cyclopropylmethyl-2H-tetrazole in dichloromethane in the presence of pyridine and DMAP (2,2-bis(hydroxymethyl)propionic acid) the corresponding compound of formula III, for example diphenylacetyl chloride or 9H-xanthene-9-carbonyl chloride is added. The reaction is carried out at about 0xc2x0 C.
The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation or pharmaceutically acceptable salts of acidic compounds.
Scheme 1 gives an overview of the manufacture of the compounds of formula I. The manufacture of representative compounds of formula I is described in detail in examples 1-28. The starting material is known or may be prepared by known methods. The compounds of formula I may be prepared in conventional manner by methods, known in the art. 
The substituents are as designated above.
The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor agonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders responsive to modulation of the metabotropic glutamate receptor, such as psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits, as well as acute and chronic pain.
Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Alzheimer""s disease, Huntington""s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
It has been shown that the compounds of the invention show agonistic activities, as measured in the assay described below, of 10 xcexcM or less, typically 1 xcexcM or less, and ideally of 0.3 xcexcM or less.